Implantation of an organ (e.g., the heart, a kidney, or a blood vessel) is often followed by a post-transplant rejection response. In an early stage of such a response, inflammation occurs in blood vessels in the transplanted organ, and in a later stage, arteriosclerosis lesions (intimal thickening) are formed. The post-transplant arteriosclerosis event is critical in clinical settings, as it leads to dysfunction of the transplanted organ and a lowered chance of successful engraftment. Although a variety of immunosuppressors have been used for management and prevention of such rejection responses, effects are not necessarily sufficient and not a few side effects result. Thus, a demand continues to exist for development of a new therapeutic method which takes into consideration the onset mechanism of the pathological conditions (Transplantation 72 (6 Suppl.): S16-9, 2001). Likewise, similar inflammatory changes are considered to participate in the intimal thickening occurring after transplantation of an auto- or allo-arteriovenous graft.
Recent research in the field of vascular biology has suggested that inflammation may be a common factor in the pathogenesis of these intractable pathological conditions (N. Engl. J. Med. 340, 115-126, 1999). Leukocytes have a function of disposal of foreign matter that has invaded the living body from the outside, and when the tissue is damaged, they come to concentrate at the damaged site, to thereby function to restore the tissue. The inflammation response is recognized as a situation where leukocytes exert their self-defense function excessively to damage the autologous tissue. For example, a coronary arteriosclerosis event occurring after heart transplantation is considered to be caused by inflammation evoked as an excessive self-defense response. This type of arteriosclerosis has an onset mechanism that clearly differs from that of ordinary arteriosclerosis, which involves infiltration of lipids and phagocytosis by macrophages on the lipids to form foamy cells.
An object of the present invention is to provide means for preventing the onset of post-transplant arteriosclerosis or post-transplant intimal thickening by preventing infiltration/accumulation of leukocytes which may otherwise occur in the implanted arteries when organ transplantation is performed.
Chemokines are a family of proteins exhibiting chemotactic activity toward leukocytes or lymphocytes. Chemokines are generally divided into four groups in terms of structure, and those having a molecular structure in which the first and second cysteines are aligned side by side are called CC chemokines.
Monocyte chemoattractant protein-1 (MCP-1), one of such CC chemokines, has itself been reported as a protein, and its cDNA sequence was elucidated at almost the same time (J. Exp. Med. 169, 1449-1459, 1989; J. Exp. Med. 169, 1485-1490, 1989; FEBS lett, 244, 487-493, 1989).
Receptors that recognize MCP-1 have been identified, and cDNA of each receptor has also been cloned (Proc. Natl. Acad. Sci. USA, 91, 2752-2756, 1994; Biochem. Biophys. Res. Commun. 202, 1156-1162, 1994). Currently, 11 CC chemokine receptors are known, and among them, an MCP-1 receptor is called CCR2.
Rollins et al. engineered amino acid mutants of the MCP-1 protein, and reported that some of them do not exhibit chemotactic activity (J. Bio. Chem. 269, 15918-15924, 1994). Of such mutants, a mutant named 7ND-MCP-1, in which amino acids 2 to 8 as counted from the N-terminus have been deleted, exhibited no chemotactic ability, although the mutant maintained the ability to bind itself to CCR2, or 7ND-MCP-1 functioned as a dominant negative to form a dimer with wild-type MCP-1, impeding the functions of MCP-1. As has also been known, a deletion occurring at the N-terminus of a chemokine can provide a strong dominant negative inhibitor against interaction with a chemokine receptor, through formation of hetero-dimers with corresponding intrinsic monomers of the chemokine, and that the inhibitor is useful for the treatment of articular rheumatism, inflammatory intestinal disease, multiple sclerosis, chronic pneumonia such as pulmonary fibrosis, and autoimmune diseases among other diseases (Japanese Kohyo (PCT) Patent Publication No. 11-506005).
Accordingly, the present invention provides a preventive and/or therapeutic agent for post-transplant arteriosclerosis occurring as a rejection response to organ transplantation or for auto- or allo-arteriovenous graft post-transplant intimal thickening, and also provides a preventive and/or therapeutic method for post-transplant arteriosclerosis occurring as a rejection response to organ transplantation or for auto- or allo-arteriovenous graft post-transplant intimal thickening.